REVIEWS
Despite the achievements of modern medicine in the diagnosis and treatment of oncological diseases, skin melanoma remains one of the leading causes of death worldwide: every third case of melanoma ends in death. As you know, one of the main causes of death is the high incidence of melanoma progression. It is important to note that the mechanisms of melanoma progression are diverse and the rapidly developing area of drug therapy for tumors requires a deep understanding of their characteristics. This is primarily due to the fact that these processes lead to the formation of special, minor tumor clones with stem properties. They are highly resistant to therapy. The latter is the mainobstacle to effective treatment of melanoma patients. The epithelial-mesenchymal transition (EMT) plays a leading role in the acquisition of metastatic potential by melanoma cells. An important distinguishing feature of EMT is a change in the level of expression of transmembrane glycoproteins involved in cell adhesion. With EMT, both a decrease in the level of E-cadherin and an increase in the expression of N-cadherin are observed. Such a switch in different classes of adhesion molecules leads to the fact that melanoma cells lose contact with neighboring keratinocytes and begin to interact with fibroblasts and endothelial cells. The key regulator in EMT induction in melanoma is the Notch1 signaling pathway, which accelerates N-cadherin expression when activated. In addition, EMT also regulates many other pathways – RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, the dysregulation of which is associated with the development of drug resistance in melanoma. The analysis was carried out in the article of modern literature data on the importance of EMT in carcinogenesis and prognosis of melanoma. The modern mechanisms of EMT, currently known prognostic factors, as well as potential therapeutic targets that affect EMT and, accordingly, inhibit the process of metastasis, are described in detail.
ORIGINAL REPORTS
Introduction. Acute myeloid leukemia (AML) is a clonal disease of the blood system that occurs as a result of mutations in the genome of hematopoietic progenitor cells. As a result of mutations, the linear differentiation of hematopoietic cells is replaced by the proliferation of malignant myeloid progenitors. Currently, the risk group for AML in children is determined mainly by the presence of specific gene and chromosomal abnormalities and an increased level of peripheral blood leukocytes. The features of the immunophenotype of blast cells can also influence the course of the disease.
The aim of the work is to assess the relationship between the immunophenotypic parameters of blast cells and the probability of achieving remission in children with AML.
Materials and methods. The study included 109 patients aged 3 months to 17 years who received treatment according to the AML BFM 87, AML BFM 2004, NII DOG AML 2007 и NII DOG AML 2012 protocol in the period from 1991 to 2020.
Results. The study showed the relationship between the probability of achieving remission and the presence of markers CD33, CD19 and CD14 on tumor cells. Expression of lymphoid antigen CD19 on blasts was associated with a higher rate of remission (73.0 % vs 95.5 %, p = 0.027). The absence of the linearly associated myeloid marker CD33 negatively correlated with the remission rate (61.1 % vs 87.7 %, p = 0.007). In the presence of monocyte antigen CD14 on blasts, the probability of achieving remission was low (95 % vs 50 %, p = 0.013).
Conclusion. Characteristics of the immunophenotype of tumor cells in AML in children are associated with the probability of achieving remission.
Introduction. Long-term monitoring of immune system parameters in cancer patient in FSBI “N.N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of Russia, as well as the absence of an immunological research algorithm and a spectrum of significant markers, served as the basis for this study.
Purpose. To present reference values and determine the normal range for subpopulations of systemic immunity lymphocytes.
Materials and methods. The phenotype of peripheral blood lymphocytes was studied in 186 healthy donors (86 men and 100 women), mean age 41,9 ± 12,5 years. To assess the multivariate phenotype by flow cytometry, monoclonal antibodies to CD45, CD3, CD4, CD8, CD16, CD56, CD19, CD25, CD28, CD11b, CD127, HLA-Dr, TCR-γ / δ, Perforin and Granzime B labeled various fluorochromes.
Results. A panel of markers of immunocompetent cells of systemic immunity was developed as a basis for assessing the state of the immune system of cancer patients. Reference values and normal boundaries are given for characterizing the linearity of cells with detailing of the phenotypic and functional heterogeneity of the population of CD8+-lymphocytes, activation markers and the pool of naive cells; characteristics of various types of regulatory cells, functional activity of cells of the effector link of immunity. A comparative analysis of immunoregulatory indices was carried out and the vulnerability of the formula CD3+CD4+/CD3+CD8+ to the CD4+/CD8+ index was proved.
Conclusion. The spectrum of the proposed indicators is the product of many years of research carried out in the laboratory of clinical immunology of the Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation, in order to search for significant criteria for assessing the state of the immune system in cancer.
Introduction. Synthetic retinoids CD437, an agonist of the gamma retinoic acid receptor (RARγ), not only induces growth arrest, but in contrast to retinoid acid, it also induces RARγ-independent apoptosis in many tumor cells through a unique mechanism that is independent of the retinoic acid receptor-mediated pathway.
The aim of the study was to study the relationship between apoptosis and autophagy in CD437-induced cell death.
Materials and methods. In this study we used 2D-culturing of lung carcinoma cells A549, immunocytochemistry, flow cytometry and fluorescence microscopy.
Results. CD437 at concentrations between 0.2 and 5.0 μM increased the number of PI-positive cells in A549 lung cancer cells. The retinoid at concentrations close to IC50 reduced the cell population in the G2/M-phase and arrest cell cycle in the S-phase. CD437 dose-dependent increased the number of apoptotic cells in the presence of non-cytotoxic concentrations of wortmanin, an irreversible inhibitor of anti-stress kinasе PI-3K, and LY 200192, a reversible inhibitor. CD437 also activated the biogenesis of autophagosomes, and there was a dose-dependent increase in the fluorescence intensity of monodansilkadaverine, a marker of autophagy. However, accumulation of LC-3B was not observed with an increase of CD437 concentration from 0.1 to 5.0 μM suggesting that the fusion between autophagic vacuoles and lysosomes was inhibited. zVAD-fmk, an irreversible caspase inhibitor, did not restore autophagy in A549 cells, and LC-3B levels did not change significantly with the increasing of CD437 concentration, indicating that CD437 was involved in autophagosome-lysosome fusion. When cells grew with non-cytotoxic concentrations of chlorokine, a late stage autophagy inhibitor, there were virtually no living cells at CD437 concentrations close to IC50. The additive effect of CD437 and chlorokine in inducing A549 cell death confirms that CD437 involved in fusion between autophagosomes and lysosomes required for final catabolism of autophagic material.
Conclusions. The data obtained indicate that CD437 induced a failure of cytoprotective function of autophagy and apoptosis, that raise the question of combined therapy of CD437 with cytotoxic drugs in the treatment of lung carcinomaIntroduction. The investigation of metal substituted organic compounds as potential antitumor drugs is one of the promising areas of research in experimental and clinical oncology.
Objective. The pre-clinical study of the original antitumor drug aurum polyacrylate (aurumacryl) which belongs to such new for oncology group of compounds as polyacrylates of metals was the aim of this work.
Materials and methods. Aurumacryl antitumor activity was determined as the tumor growth inhibitory effect against some of the murine solid tumors (Lewis lung carcinoma, Acatol adenocarcinoma and Ca-755 adenocarcinoma). Drug cytotoxic effect against some of the human tumor cells (Mel-Mo melanoma, A549 lung carcinoma, MCF-7 breast carcinoma, HCT116 colon adenocarcinoma) was evaluated with standard МТТ-test. The aurumacryl pharmacokinetics in tumor bearing mice (Lewis lung carcinoma) was studied. The inductively coupled plasma mass spectrometry method was used for the estimation of the aurum maintenance in the tested tissues (tumor, blood, kidneys, liver, lungs, spleen, brain).
Results. The 80–90 % tumor growth inhibitory effect of aurumacryl against some solid tumors in mice had been revealed in vivo as well as the death of the 60–90 % human tumor cells of various origins in vitro. Beside this the strong decrease of the number of proliferating MCF-7 tumor cells had been shown. The distribution of aurumacryl in the body of the mice with the solid tumor had been revealed.
Conclusion. On the base of the data obtained the further study of the aurumacryl as a potential antitumor agent seems rather promising.
Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.
The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.
Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.
Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).
Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).
ISSN 1726-9792 (Online)